Therapeutic cyclopentane derivatives

ABSTRACT

Described herein are compounds having a formula 
                         
and therapeutic methods, compositions, and medicaments, related thereto.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/746,391, filed May 4, 2006, the disclosure of which is herebyincorporated in its entirety herein by reference.

BACKGROUND

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein Y is an organic acid functional group, or an amide or ester    thereof comprising up to 14 carbon atoms; or Y is hydroxymethyl or    an ether thereof comprising up to 14 carbon atoms; or Y is a    tetrazolyl functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O; and-   B is substituted aryl or substituted heteroaryl.

Also disclosed herein is a carboxylic acid or a bioisostere thereof,said carboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—,    wherein 1 or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O; and-   B is substituted aryl or substituted heteroaryl.

“Bioisosteres are substituents or groups that have chemical or physicalsimilarities, and which produce broadly similar biological properties.”Silverman, Richard B., The Organic Chemistry of Drug Design and DrugAction, 2^(nd) Edition, Amsterdam: Elsevier Academic Press, 2004, p. 29.

While not intending to be limiting, organic acid functional groups arebioisoteres of carboxylic acids. An organic acid functional group is anacidic functional group on an organic molecule. While not intending tobe limiting, organic acid functional groups may comprise an oxide ofcarbon, sulfur, or phosphorous. Thus, while not intending to limit thescope of the invention in any way, in certain compounds Y is acarboxylic acid, sulfonic acid, or phosphonic acid functional group.

Additionally, an amide or ester of one of the organic acids shown abovecomprising up to 14 carbon atoms is also contemplated. In an ester, ahydrocarbyl moiety replaces a hydrogen atom of an acid such as in acarboxylic acid ester, e.g. CO₂Me, CO₂Et, etc.

In an amide, an amine group replaces an OH of the acid. Examples ofamides include CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, and CON H(CH₂CH₂OH)where R² is independently H, C₁-C₆ alkyl, phenyl, or biphenyl. Moietiessuch as CONHSO₂R² are also amides of the carboxylic acid notwithstandingthe fact that they may also be considered to be amides of the sulfonicacid R²—SO₃H. The following amides are also specifically contemplated,CONSO₂-biphenyl, CONSO₂-phenyl, CONSO₂-heteroaryl, and CONSO₂-naphthyl.The biphenyl, phenyl, heteroaryl, or naphthyl may be substituted orunsubstituted.

Han et. al. (Biorganic & Medicinal Chemistry Letters 15 (2005)3487-3490) has recently shown that the groups shown below are suitablebioisosteres for a carboxylic acid. The activity of compounds with thesegroups in inhibiting HCV NS3 protease was comparable to or superior tosimilar compounds where the group is replaced by CO₂H. Thus, Y could beany group depicted below.

Carboxylic Acid Bioisosteres According to Han et. al.

While not intending to limit the scope of the invention in any way, Ymay also be hydroxymethyl or an ether thereof comprising up to 14 carbonatoms. An ether is a functional group wherein a hydrogen of an hydroxylis replaced by carbon, e.g., Y is CH₂OCH₃, CH₂OCH₂CH₃, etc. These groupsare also bioisosteres of a carboxylic acid.

“Up to 14 carbon atoms” means that the entire Y moiety, including thecarbonyl carbon of a carboxylic acid ester or amide, and both carbonatoms in the —CH₂O—C of an ether has 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 carbon atoms.

Finally, while not intending to limit the scope of the invention in anyway, Y may be a tetrazolyl functional group.

While not intending to be limiting, examples of compounds having theidentified Y are depicted below. In these examples R is H orhydrocarbyl, subject to the constraints defined herein. Each structurebelow represents a specific embodiment which is individuallycontemplated, as well as pharmaceutically acceptable salts and prodrugsof compounds which are represented by the structures. However, otherexamples are possible which may not fall within the scope of thestructures shown below.

Organic Acids Esters Amides

A tetrazolyl functional group is another bioisostere of a carboxylicacid. An unsubstituted tetrazolyl functional group has two tautomericforms, which can rapidly interconvert in aqueous or biological media,and are thus equivalent to one another. These tautomers are shown below.

Additionally, if R² is C₁-C₆ alkyl, phenyl, or biphenyl, other isomericforms of the tetrazolyl functional group such as the one shown below arealso possible, unsubstituted and hydrocarbyl substituted tetrazolyl upto C₁₂ are considered to be within the scope of the term “tetrazolyl.”

While not intending to limit the scope of the invention in any way, inone embodiment, Y is CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

According to Silverman (p. 30), the moieties shown below are alsobioisosteres of a carboxylic acid.

Carboxylic Acid Bioisosteres According to Silverman

Orlek et al. (J. Med. Chem. 1991, 34, 2726-2735) described oxadiazolesas suitable bioisosteres for a carboxylic acid. These ester replacementswere shown to be potent muscarinic agonists having improved metabolicstability. Oxadiazoles were also described by Anderson et al. (Eur. J.Med. Chem. 1996, 31, 417-425) as carboxamide replacements havingimproved in vivo efficacy at the benzodiazepine receptor.

Carboxylic Acid Bioisosteres According to Orlek et. al.

Kohara et al. (J. Med. Chem. 1996, 39, 5228-5235) described acidicheterocycles as suitable bioisosteres for a tetrazole. These carboxylicacid replacements were shown to be potent angiotensin II receptorantagonists having improved metabolic stability.

Tetrazole Bioisosteres According to Kohara et. al.

Drysdale et al. (J. Med. Chem. 1992, 35, 2573-2581) have describedcarboxylic acid mimics of non-peptide CCK-B receptor antagonists. Thebinding affinities of many of the bioisosteres are similar to the parentcarboxylic acid.

Carboxylic Acid Bioisosteres According to Drysdale et. al.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein oneCH₂ may be replaced with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be a moiety where S replaces one or two carbon atoms such as one ofthe following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way,

-   in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar,    e.g. —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—,    —(CH₂)₂—Ar—(CH₂)₂—, and the like;-   in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties;    and Ar, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,    —O—CH₂—Ar—(CH₂)₂, and the like; or-   in another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties;    and Ar, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,    —S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

-   hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,    alkenyl, alkynyl, and the like;-   hydrocarbyloxy up to C₃;-   organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and salts    thereof;-   CF₃;-   halo, such as F, Cl, or Br;-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents such as CN, NO₂, and the like;-   and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is 1, 2, or 3, and wherein one CH₂may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar isattached at the 1 and 3 positions, otherwise known as m-interphenylene,such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂—O—(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-(methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below, andpharmaceutically acceptable salts thereof, and prodrugs thereof, arecontemplated as individual embodiments. In other words, each structurerepresents a different embodiment.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt. Thus, while not intending to limit the scope of the invention inany way, a substituent may be:

-   hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen    such as alkyl, alkenyl, alkynyl, and the like, including linear,    branched or cyclic hydrocarbyl, and combinations thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 19 carbon atoms;-   other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the    like;-   thioether substituents including S-hydrocarbyl and other thioether    substituents;-   hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,    etc, up to 19 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 19    carbon atoms;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like-   fluorocarbyl, such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl. For this type ofpolycyclic ring system, an aromatic or heteroaromatic ring, not anon-aromatic ring, must be attached to the remainder of the molecule. Inother words, in any structure depicting —B herein, where—is a bond, thebond is a direct bond to an aromatic ring.

In one embodiment, B is substituted aryl or heteroaryl.

In another embodiment B is substituted phenyl.

In another embodiment B has no halogen atoms.

In another embodiment B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

In another embodiment B is 4-(1-hydroxy-2-methylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxybutyl)phenyl.

In another embodiment B is 4-(1-hydroxyheptyl)phenyl.

In another embodiment B is 4-(1-hydroxyhexyl)phenyl.

In another embodiment B is 4-(1-hydroxypentyl)phenyl.

In another embodiment B is 4-(1-hydroxypropyl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

In another embodiment B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

In another embodiment B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 2,3-dihydro-1H-inden-5-yl.

In another embodiment B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

In another embodiment B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

In another embodiment B is 4-tert-butylphenyl.

In another embodiment B is 4-hexylphenyl.

In another embodiment B is 4-(1-hydroxy-2-phenylethyl)phenyl.

In another embodiment B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

In another embodiment B is 4-(1-hydroxycyclobutyl)phenyl.

In another embodiment B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

In another embodiment B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

In another embodiment B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

In another embodiment B is 4-(cyclohexylmethyl)phenyl.

In another embodiment B is 4-(hydroxy(phenyl)methyl)phenyl.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.    Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.    Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.    Another embodiment is a compound according to the structure

Another embodiment is a compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein A¹ is —(CH₂)₃—, —OCH₂CH₂—, —CH₂OCH₂—, —(CH₂)₂O—, —OCH₂CH₂—,    —CH₂OCH₂—, or —(CH₂)₂O—;-   X¹ is O or S; and-   X² is N, O, or S.

Another embodiment is a compound having a structure

wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

-   Alkyl is hydrocarbyl having no double or triple bonds including:-   linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl,    n-hexyl, and the like;-   branched alkyl such as isopropyl, branched butyl isomers (i.e.    sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e.    isopentyl, etc), branched hexyl isomers, and higher branched alkyl    fragments;-   cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.; and alkyl fragments consisting of both cyclic and    noncyclic components, whether linear or branched, which may be    attached to the remainder of the molecule at any available position    including terminal, internal, or ring carbon atoms.-   Alkenyl is hydrocarbyl having one or more double bonds including-   linear alkenyl, branched alkenyl, cyclic alkenyl, and combinations    thereof in analogy to alkyl.-   Alkynyl is hydrocarbyl having one or more triple bonds including    linear alkynyl, branched alkynyl, cyclic alkynyl and combinations    thereof in analogy to alkyl.-   Aryl is an unsubstituted or substituted aromatic ring or ring system    such as phenyl, naphthyl, biphenyl, and the like. Aryl may or may    not be hydrocarbyl, depending upon whether it has substituents with    heteroatoms.-   Arylalkyl is alkyl which is substituted with aryl. In other words    alkyl connects aryl to the remaining part of the molecule. Examples    are —CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may    not be hydrocarbyl, depending upon whether it has substituents with    heteroatoms. Unconjugated dienes or polyenes have one or more double    bonds which are not conjugated. They may be linear, branched, or    cyclic, or a combination thereof.    Combinations of the above are also possible.

Thus, each of the structures below is contemplated. These structures, orpharmaceutically acceptable salts thereof, or prodrugs thereof,individually represent a compound which is an embodiment contemplatedherein. In other words, each structure represents a differentembodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

Hypothetical examples of useful compounds are shown below.

Other useful compounds include:

-   (Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid (4);-   (Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid isopropyl ester (5);-   (Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid methyl ester;-   (Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid (8);-   (Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid methyl ester; and-   (Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoic    acid isopropyl ester.

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein Y is an organic acid functional group, or an amide or ester    thereof comprising up to 14 carbon atoms; or Y is hydroxymethyl or    an ether thereof comprising up to 14 carbon atoms; or Y is a    tetrazolyl functional group;-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O; and-   B is substituted aryl or substituted heteroaryl.

Compound Example 2

The compound according to compound example 1 wherein Y is selected fromCO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂, CONH(CH₂CH₂OH), CH₂OH,P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.

Compound Example 3

The compound according to compound example 1 or 2 wherein B issubstituted phenyl.

Compound Example 4

The compound according to compound example 1 or 2 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 5

The compound according to compound example 4 wherein R is alkyl.

Compound Example 6

The compound according to compound example 4 wherein R is arylalkyl.

Compound Example 7

The compound according to compound example any one of compound examples1 to 6 having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   R is hydrogen or C₁₋₁₀ hydrocarbyl.

Compound Example 8

The compound according to compound example 1 or 2 wherein A is(3-methylphenoxy)methyl.

Compound Example 9

The compound according to compound example 1 or 2 wherein A is(4-but-2-ynyloxy)methyl.

Compound Example 10

The compound according to compound example 1 or 2 wherein A is2-(2-ethylthio)thiazol-4-yl.

Compound Example 11

The compound according to compound example 1 or 2 wherein A is2-(3-propyl)thiazol-5-yl.

Compound Example 12

The compound according to compound example 1 or 2 wherein A is3-(methoxymethyl)phenyl.

Compound Example 13

The compound according to compound example 1 or 2 wherein A is3-(3-propylphenyl.

Compound Example 14

The compound according to compound example 1 or 2 wherein A is3-methylphenethyl.

Compound Example 15

The compound according to compound example 1 or 2 wherein A is4-(2-ethyl)phenyl.

Compound Example 16

The compound according to compound example 1 or 2 wherein A is4-phenethyl.

Compound Example 17

The compound according to compound example 1 or 2 wherein A is4-methoxybutyl.

Compound Example 18

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)furan-2-yl.

Compound Example 19

The compound according to compound example 1 or 2 wherein A is5-(methoxymethyl)thiophen-2-yl.

Compound Example 20

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)furan-2-yl.

Compound Example 21

The compound according to compound example 1 or 2 wherein A is5-(3-propyl)thiophen-2-yl.

Compound Example 22

The compound according to compound example 1 or 2 wherein A is 6-hexyl.

Compound Example 23

The compound according to compound example 1 or 2 wherein A is(Z)-6-hex-4-enyl.

Compound Example 24

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2,2-dimethylpropyl)phenyl.

Compound Example 25

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropan-2-yl)phenyl.

Compound Example 26

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 27

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxybutyl)phenyl.

Compound Example 28

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyheptyl)phenyl.

Compound Example 29

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxyhexyl)phenyl.

Compound Example 30

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypentyl)phenyl.

Compound Example 31

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxypropyl)phenyl.

Compound Example 32

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methylheptan-2-yl)phenyl.

Compound Example 33

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-hydroxy-2-methyloctan-2-yl)phenyl.

Compound Example 34

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 1-hydroxy-2,3-dihydro-1H-inden-5-yl.

Compound Example 35

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 2,3-dihydro-1H-inden-5-yl.

Compound Example 36

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 3-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 37

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-5,5-dimethylhexyl)phenyl.

Compound Example 38

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(1-propylcyclobutyl)methyl)phenyl.

Compound Example 39

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-tert-butylphenyl.

Compound Example 40

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-hexylphenyl.

Compound Example 41

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 42

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxy-3-phenylpropyl)phenyl.

Compound Example 43

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(1-hydroxycyclobutyl)phenyl.

Compound Example 44

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(2-cyclohexyl-1-hydroxyethyl)phenyl.

Compound Example 45

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(3-cyclohexyl-1-hydroxypropyl)phenyl.

Compound Example 46

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexyl(hydroxy)methyl)phenyl.

Compound Example 47

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(cyclohexylmethyl)phenyl.

Compound Example 48

The compound according to any one of compound examples 1, 2, and 8-23wherein B is 4-(hydroxy(phenyl)methyl)phenyl.

Compound Example 49

A compound which is a carboxylic acid or a bioisostere thereof, saidcarboxylic acid having a structure

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

-   wherein A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—,    wherein 1 or 2 carbon atoms may be replaced by S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein    one CH₂ may be replaced by S or O; and-   B is substituted aryl or substituted heteroaryl.    The following are hypothetical examples of compositions, kits,    methods, uses, and medicaments employing the hypothetical compound    examples.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 49, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 49 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

A medicament comprising a compound according to any one of compoundexamples 1 to 49, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 49 to a mammal for the treatment of glaucoma orocular hypertension.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 49, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjuster 1-10 buffer 0.01-10 pH adjusterq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

-   β-Blockers (or β-adrenergic antagonists) including carteolol,    levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,    β1-selective antagonists such as betaxolol, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   Adrenergic Agonists including-   non-selective adrenergic agonists such as epinephrine borate,    epinephrine hydrochloride, and dipivefrin, and the like, or    pharmaceutically acceptable salts or prodrugs thereof; and-   α₂-selective adrenergic agonists such as apraclonidine, brimonidine,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Carbonic Anhydrase Inhibitors including acetazolamide,    dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the    like, or pharmaceutically acceptable salts or prodrugs thereof;-   Cholinergic Agonists including-   direct acting cholinergic agonists such as carbachol, pilocarpine    hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   chlolinesterase inhibitors such as demecarium, echothiophate,    physostigmine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   Glutamate Antagonists and other neuroprotective agents such as Ca²⁺    channel blockers such as memantine, amantadine, rimantadine,    nitroglycerin, dextrophan, detromethorphan, CGS-19755,    dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,    diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related    drugs, fluspirilene, eliprodil, ifenprodil, CP-101, 606, tibalosine,    2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,    barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Prostamides such as bimatoprost, or pharmaceutically acceptable    salts or prodrugs thereof; and-   Prostaglandins including travoprost, UFO-21, chloprostenol,    fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone,    latanoprost and the like.-   Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940    and the like, or pharmaceutically acceptable salts or prodrugs    thereof.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

In addition to the treatment of glaucoma, prostaglandin EP₂ selectiveagonists are believed to have several medical uses. For example, U.S.Pat. No. 6,437,146 teaches the use of prostaglandin EP₂ selectiveagonists “for treating or preventing inflammation and pain in joint andmuscle (e.g., rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatoryskin condition (e.g., sunburn, burns, eczema, dermatitis, etc.),inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorderin which inflammation is involved (e.g., asthma, bronchitis, pigeonfancier's disease, farmer's lung, etc.), condition of thegastrointestinal tract associated with inflammation (e.g., aphthousulcer, Chrohn's disease, atrophic gastritis, gastritis varialoforme,ulcerative colitis, coeliac disease, regional ileitis, irritable bowelsyndrome, etc.), gingivitis, inflammation, pain and tumescence afteroperation or injury, pyrexia, pain and other conditions associated withinflammation, allergic disease, systemic lupus crythematosus,scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose,rheumatic fever, Sjgren's syndrome, Behcet disease, thyroiditis, type Idiabetes, diabetic complication (diabetic microangiopathy, diabeticretinopathy, diabetic neohropathy, etc.), nephrotic syndrome, aplasticanemia, myasthenia gravis, uveitis contact dermatitis, psoriasis,Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease,kidney dysfunction (nephritis, nephritic syndrome, etc.), liverdysfunction (hepatitis, cirrhosis, etc.), gastrointestinal dysfunction(diarrhea, inflammatory bowel disease, etc.) shock, bone diseasecharacterized by abnormal bone metabolism such as osteoporosis(especially, postmenopausal osteoporosis), hypercalcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodonritis, osteoarthritis, ostealgia, osteopenia, cancer cachexia,calculosis, lithiasis (especially, urolithiasis), solid carcinoma,mesangial proliferative glomerulonephritis, edema (e.g. cardiac edema,cerebral edema, etc.), hypertension such as malignant hypertension orthe like, premenstrual tension, urinary calculus, oliguria such as theone caused by acute or chronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

These compounds can also be used to treat or prevent conditionsaffecting the posterior part of the eye including maculopathies/retinaldegeneration such as non-exudative age related macular degeneration(ARMD), exudative age related macular degeneration (ARMD), choroidalneovascularization, diabetic retinopathy, acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; uveitis/retinitis/choroiditis such asacute multifocal placoid pigment epitheliopathy, Behcet's disease,birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vasuclar diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, disseminated intravascularcoagulopathy, branch retinal vein occlusion, hypertensive funduschanges, ocular ischemic syndrome, retinal arterial microaneurysms,Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion,papillophlebitis, central retinal artery occlusion, branch retinalartery occlusion, carotid artery disease (CAD), frosted branch angiitis,sickle cell retinopathy and other hemoglobinopathies, angioid streaks,familial exudative vitreoretinopathy, and Eales disease;traumatic/surgical conditions such as sympathetic ophthalmia, uveiticretinal disease, retinal detachment, trauma, conditions caused by laser,conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (POHS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with associated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.Preferably, the disease or condition is retinitis pigmentosa,proliferative vitreal retinopathy (PVR), age-related maculardegeneration (ARMD), diabetic retinopathy, diabetic macular edema,retinal detachment, retinal tear, uveitus, or cytomegalovirus retinitis.

These compounds are also useful in treating asthma.

4-Nitro-benzoic acid(1S,2S,3R,4R)-2-[4-(1-acetoxy-hexyl)-phenyl]-4-chloro-3-((Z)-6-methoxycarbonyl-hex-2-enyl)-cyclopentylester (1)

Compound 1 was prepared as described in the CIP for application 17693.

(Z)-7-{(1R,2S,3S,5R)-2-[4-(1-Acetoxy-hexyl)-phenyl]-5-chloro-3-hydroxy-cyclopentyl}-hept-5-enoicacid methyl ester (2)

K₂CO₃ (20 mg, 0.15 mmol) was added to a solution of 1 (88 mg, 0.14 mmol)in methanol (4 mL). The mixture was stirred at room temperature for 45min., and then saturated NH₄Cl solution (20 mL) was added. The resultingmixture was extracted with ethyl acetate (3×30 mL) and the combinedethyl acetate solution was dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by flash chromatography on silica gel (25%→40%ethyl acetate/hexanes) which gave 2 (34 mg, 51%) along with the diolcorresponding to 2 (20 mg, 32%).

(Z)-7-{(1R,2S,3R,5R)-2-[4-(1-Acetoxy-hexyl)-phenyl]-3,5-dichloro-cyclopentyl}-hept-5-enoicacid methyl ester (3)

Compound 3 was prepared using the previously described (U.S. patentapplication Ser. No. 11/009,298, filed on Dec. 10, 2004, which isexpressly incorporated by reference herein)MsCl/(n-Bu)₄NCl procedure.

(Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid (4)

The previously described (U.S. patent application Ser. No. 11/009,298)aq. LiOH procedure was used.

(Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid isopropyl ester (5)

The previously described 2-iodopropane/DBU procedure was used (U.S.patent application Ser. No. 11/009,298).

(Z)-7-{(1R,2S,3R,5R)-2-[4-(1-Acetoxy-hexyl)-phenyl]-5-chloro-3-hydroxy-cyclopentyl}-hept-5-enoicacid methyl ester (6)

Compound 6 was prepared as described in U.S. Provisional PatentApplication No. 60/742,779, filed on Dec. 6, 2005, which is expresslyincorporated herein by reference.

(Z)-7-{(1R,2S,3S,5R)-2-[4-(1-Acetoxy-hexyl)-phenyl]-3,5-dichloro-cyclopentyl}-hept-5-enoicacid methyl ester (7)

The mesylate corresponding to 6 was prepared using the previouslydescribed procedure (application 17693). The crude mesylate (0.050 mmol)was taken into 1 mL toluene, (n-Bu)₄NCl (150 mg, 0.54 mmol) was addedand the resulting mixture was heated at 55° C. for 2 days. At this time,the mixture was filtered through a pad of silica gel (ethyl acetate) andthe filtrate was evaporated. The residue was purified by flashchromatography on silica gel (15% ethyl acetate/hexanes) which gave thetitle compound (10 mg, 41% from 6).

(Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid (8)

The previously described (U.S. patent application Ser. No. 11/009,298)aq. LiOH procedure was used.

Compounds such as those depicted in the structure on the right below maybe prepared as described in Krishnamurti as depicted below. Use ofprotecting groups for additional carbonyl groups which can be part of M⁴may be necessary. Standard protection and deprotection is known in theart to carry this out. The fluoroalkylation may also be carried out anearlier point in the synthetic procedure. Such decisions are well withinthe knowledge of one of ordinary skill in the art.

Biology Examples

Binding Data

Ki

Competition binding experiments were performed in a medium containingHank's balanced salt solution, Hepes 20 mM, pH 7.3, membranes (˜60 μgprotein) or 2×10⁵ cells from HEK 293 cells stably expressing human EP2receptors, [³H]PGE2 (10 nM) and various concentrations of test compoundsin a total volume of 300 μl. Reaction mixtures were incubated at 23° C.for 60 min, and were filtered over Whatman GF/B filters under vacuum.Filters were washed three times with 5 ml ice-cold buffer containing 50mM Tris/HCl (pH 7.3). Non-specific binding was estimated in the presenceof excess unlabeled PGE2 (10 μM). Binding data fitted to the bindingmodel for a single class of binding sites, using nonlinear regressionanalysis. IC₅₀ values thus obtained were converted to Ki using theequation of Ki=(IC₅₀/(1+[L]/K_(D)) where [L] represents PGE2concentration (10 nM) and K_(D) the dissociation constant for [³H]PGE2at human EP2 receptors (40 nM).

Radioligand Binding

Cells Stably Expressing EP₁, EP₂, EP₄ and FP Receptors

HEK-293 cells stably expressing the human or feline FP receptor, or EP₁,EP₂, or EP₄ receptors were washed with TME buffer, scraped from thebottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at 4° C.using a Beckman Ti-60 rotor. The resultant pellet was resuspended in TMEbuffer to give a final 1 mg/ml protein concentration, as determined byBiorad assay. Radioligand binding competition assays vs. [³H-]17-phenylPGF₂

(5 nM) were performed in a 100 μl volume for 60 min. Binding reactionswere started by adding plasma membrane fraction. The reaction wasterminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapidfiltration through glass fiber GF/B filters using a Brandel cellharvester. The filters were washed 3 times with ice-cold buffer and ovendried for one hour.

[³H-] PGE₂ (specific activity 180 Ci mmol) was used as the radioligandfor EP receptors. [³H] 17-phenyl PGF₂

was employed for FP receptor binding studies. Binding studies employingEP₁, EP₂, EP₄ and FP receptors were performed in duplicate in at leastthree separate experiments. A 200 μl assay volume was used. Incubationswere for 60 min at 25° C. and were terminated by the addition of 4 ml ofice-cold 50 mM TRIS-HCl, followed by rapid filtration through WhatmanGF/B filters and three additional 4 ml washes in a cell harvester(Brandel). Competition studies were performed using a finalconcentration of 5 nM [³H]-PGE₂, or 5 nM [³H] 17-phenyl PGF₂

and non-specific binding determined with 10⁻⁵M of unlabeled PGE₂, or17-phenyl PGF₂

, according to receptor subtype studied.

Methods for FLIPR™ Studies

(a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hiP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM l-glutamine, 250

g/ml geneticin (G418) and 200

g/ml hygromycin B as selection markers, and 100 units/ml penicillin G,100

g/ml streptomycin and 0.25

g/ml amphotericin B.

(b) Calcium Signal Studies on the FLIPR™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2

M, plates were washed four times with HBSS-HEPES buffer to remove excessdye leaving 100

l in each well. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50

l volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF₂

(hFP); carbacyclin (hIP); U-46619 (hTP), depending on receptor). Thepeak fluorescence change in each drug-containing well was then expressedrelative to the controls.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3.

cAMP Assay

A 384-well drug plate was prepared to contain 6 test compounds, PGE2 andcAMP in 16 serial dilutions in triplicate, using a Biomek station.HEK-EBNA cells expressing a target PG receptor subtype (EP2 or EP4) weresuspended in a stimulation buffer (HBSS, 0.1% BSA, 0.5 mM IBMX and 5 mMHEPES, pH 7.4) in a density of 10⁴ cells/5 μl. The reaction wasinitiated by mixing 5 μL drug dilutions with 5 μl of HEK-EBNA cells in awell, carried out for 30 min at room temperature, and followed by theaddition of 5 μl anti-cAMP acceptor beads in the control buffer withTween-20 (25 mM NaCl, 0.03% Tween-20, 5 mM HEPES, pH7.4). After 30 minin the dark at room temperature, the mixtures were incubated with 15 μlbiotinylated-cAMP/strepavidin donor beads in Lysis/Detection buffer(0.1% BSA, 0.3% Tween-20 and 5 mM HEPES, pH7.4) for 45 min at the roomtemperature. Fluorescence changes were read using a Fusion-alpha HTmicroplate reader.

The results of the binding and activity studies, presented in Table 1below, demonstrate that the compounds disclosed herein are selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, and other diseases or conditions.

TABLE 1 BINDING-Ki (nM) Ca²⁺ Signal-EC50 (nM)^(b) ENTRY STRUCTURE^(a)EP2 EP4 FP EP1 EP2 EP3 EP4 TP IP DP 1

504 2364 notactive notactive 427(58) 449 >10,000 notactive notactivenotactive 2

 25 1400 notactive notactive  15(4)  25 not active notactive notactivenotactive

In vivo testing done as described in U.S. patent application Ser. No.11/009,298 gave the results in Table 2 below.

TABLE 2 DOG MONKEY RABBIT Conc. Max. □□ Max. Max.□IOP Max. ENTRYSTRUCTURE (g/100 mL) OP (%) hyperemia (%) hyperemia 1

0.1% −12 0.6 19 0.0

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,commercially provides pH dependent methacrylate based polymers andcopolymers which have varying solubilities over different pH rangesbased upon the number of free carboxylate groups in the polymer underthe tradename Eudragit®. Several Eudragit® dosage forms are currentlyused to deliver salsalazine for the treatment of ulcerative colitis andCrohn's disease. Time release systems, bioadhesive systems, and otherdelivery systems have also been studied.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein Y is an organicacid functional group, or an amide or ester thereof comprising up to 14carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to14 carbon atoms; or Y is a tetrazolyl functional group; A is —(CH₂)₆—,cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atomsmay be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Aris interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or4, and wherein one CH₂ may be replaced by S or O; and B is substitutedaryl or substituted heteroaryl.
 2. The compound of claim 1 wherein Y isselected from CO₂R², CON(R²)₂, CON(OR²)R², CON(CH₂CH₂OH)₂,CONH(CH₂CH₂OH), CH₂OH, P(O)(OH)₂, CONHSO₂R², SO₂N(R²)₂, SO₂NHR²,

wherein R² is independently H, C₁-C₆ alkyl, unsubstituted phenyl, orunsubstituted biphenyl.
 3. The compound of claim 2 wherein B issubstituted phenyl.
 4. The compound of claim 3 of the formula

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen orC₁₋₁₀ hydrocarbyl.
 5. The compound of claim 4 wherein R is alkyl.
 6. Thecompound of claim 1 of the formula

or a pharmaceutically acceptable salt thereof, wherein A¹ is —(CH₂)₃—,—OCH₂CH₂—, —CH₂OCH₂—, or —(CH₂)₂O—; X¹ is O or S; and X² is N, O, or S.7. The compound of claim 6 of the formula

wherein R is hydrogen or C₁₋₁₀ hydrocarbyl.
 8. The compound of claim 4of the formula

or a pharmaceutically acceptable salt thereof; R is hydrogen or C₁₋₁₀hydrocarbyl.
 9. The compound of claim 1 wherein A is(3-methylphenoxy)methyl.
 10. The compound of claim 1 wherein A is2-(2-ethylthio)thiazol-4-yl.
 11. The compound of claim 1 wherein A is2-(3-propyl)thiazol-5-yl.
 12. The compound of claim 1 wherein A is5-(methoxymethyl)furan-2-yl.
 13. The compound of claim 1 wherein A is5-(methoxymethyl)thiophen-2-yl.
 14. The compound of claim 1 wherein A is5-(3-propyl)furan-2-yl.
 15. The compound of claim 1 wherein A is5-(3-propyl)thiophen-2-yl.
 16. The compound of claim 1 wherein A is6-hexyl.
 17. The compound of claim 1 wherein A is (Z)-6-hex-4-enyl. 18.The compound of claim 1, selected from the group consisting of(Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid;(Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid isopropyl ester;(Z)-7-{(1R,2S,3R,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid methyl ester;(Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid;(Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid methyl ester; and(Z)-7-{(1R,2S,3S,5R)-3,5-Dichloro-2-[4-(1-hydroxy-hexyl)-phenyl]-cyclopentyl}-hept-5-enoicacid isopropyl ester.
 19. A method comprising administering a compoundaccording to claim 1 to a mammal for the treatment of glaucoma or ocularhypertension.
 20. A composition comprising a compound according to claim1, wherein said composition is a liquid which is ophthalmicallyacceptable.